Aminoglycosides are clinically used drugs that cause dose-dependent sensorineural hearing loss (Smith et al., New Engl J Med, (1977) 296:349-53) and are known to kill hair cells in the mammalian inner ear (Theopold, Acta Otolaryngol (1977) 84:57-64). In the U.S. over 2,000,000 people receive treatment with aminoglycosides per year. The clinical efficacy of these drugs in treating resistant bacterial infections and their low cost globally account for their continued use and need. Cisplatin, a chemotherapeutic agent is also used for its benefit to life despite its toxic effects on the hair cells of the inner ear. High frequency hearing loss (>8 kHZ) has been reported to be as high as 90% in children undergoing cisplatin therapy (Allen, et al, Otolaryngol Head Neck Surg (1998) 118:584-588). The incidence of vestibulotoxic effects of such drugs on patient populations has been less well studied. Estimates range between 3% and 6% with continued reports in the literature of patients with aminoglycoside induced vestibulotoxicity (Dhanireddy et al., Arch Otolarngol Head Neck Surg (2005) 131:46-48). Other clinically important and commonly used drugs also have documented ototoxic effects, including loop diuretics (Greenberg, Am J Med Sci, (2000) 319:10-24), antimalarial sesquiterpene lactone endoperoxides (i.e., artemesinins) (Toovey and Jamieson, Trans R Soc Trop Med Hyg (2004) 98:261-7), antimalarial quinines (Claessen, et al., Trop Med Int Health, (1998) 3:482-9), salicylates (Matz, Ann Otol Rhinol Laryngol Suppl (1990) 148:39-41), and interferon polypeptides (Formann, et al., Am J Gastroenterol (2004) 99:873-77).
Zebrafish are an advantageous animal model for studying hair cell development and function (see, Grant et al., Neuron (2005) 45:89-80). U.S. Pat. No. 6,656,449 discloses general methods of screening unknown agents in zebrafish for cell death activity, but does not describe preferential labeling of any particular tissue or cell type in a live zebrafish. Idziorek, et al., disclose that the cell impermeant nuclear dye YOPRO-1 (Molecular Probes, Eugene, Oreg.) does not interfere with cell viability of human immune cells, but does not disclose labeling zebrafish or hair cells. Harris, et al., disclose exposing zebrafish lateral hair cells labeled with the fluorescent vital dye DASPEI to neomycin and identifying regenerating hair cells (J Assoc Res Otolaryngol (2003) 4:219-34). Harris, et al., assert to have provided a preparation for studying and identifying genes that influence vertebrate hair cell death. None of the foregoing references disclose using zebrafish for screening for compounds that inhibit or prevent ototoxicity induced by one or more noxious stimuli. Accordingly, there remains a need for the identification of compounds that can counteract sensory hair cell loss. The present invention fulfills this and other needs.